TW201307293A - New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid - Google Patents
New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid Download PDFInfo
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Abstract
Description
本發明係關於一種合成式(I)依伐布雷定(ivabradine):
依伐布雷定及其與醫藥上可接受酸之加成鹽(及更特定言之其鹽酸鹽)具有非常重要的藥理及治療特性(尤其係心搏徐緩特性),其使得彼等化合物可有效治療或預防心肌局部缺血之各種臨床狀況(例如心絞痛、心肌梗塞及相關節律紊亂)及包括節律紊亂(尤其係室上性節律紊亂)之各種病狀及心臟衰竭。 Ivabradine and its addition salts with pharmaceutically acceptable acids (and more particularly its hydrochloride) have very important pharmacological and therapeutic properties (especially bradycardia properties) which allow their compounds to Effectively treats or prevents various clinical conditions of myocardial ischemia (such as angina pectoris, myocardial infarction, and related rhythm disorders) and various conditions including heart rhythm disorders (especially supraventricular rhythm disorders) and heart failure.
歐洲專利說明書EP 0 534 859已描述依伐布雷定及其與醫藥上可接受酸之加成鹽(及更特定言之其鹽酸鹽)之製法及治療用途。 European Patent Specification EP 0 534 859 describes the preparation and therapeutic use of ivabradine and its addition salts with pharmaceutically acceptable acids (and more particularly its hydrochloride).
該專利說明書描述自式(II)化合物開始來合成依伐布雷定鹽酸鹽:
該合成途徑之缺點係其產生僅1%產率之依伐布雷定。 A disadvantage of this synthetic route is that it produces ivabradine with a yield of only 1%.
鑒於此化合物之醫藥價值,能夠藉由具有良好依伐布雷定產率之有效合成方法來獲得此化合物係非常重要。 In view of the pharmaceutical value of this compound, it is very important to be able to obtain this compound by an efficient synthesis method with good ivabradine yield.
本發明係關於一種合成式(I)依伐布雷定之方法:
可用於進行還原胺化反應之一系列還原劑可參考著作 「Comprehensive Organic Transformations」(Richard C.Larock,VCH出版社1989,421-425頁)及「Advanced Organic Chemistry Fourth Edition」(Jerry March,Wiley Interscience 1992,898-900頁)。 A series of reducing agents that can be used in the reductive amination reaction can be found in the book " Comprehensive Organic Transformations " (Richard C. Larock, VCH Press, 1989, pages 421-425) and " Advanced Organic Chemistry Fourth Edition " (Jerry March, Wiley Interscience). 1992, 898-900 pages).
在可用於進行式(VI)化合物與式(VII)化合物之還原胺化反應之還原劑中,可提及(不意味任何限制)三乙醯氧基硼氫化鈉、氰基硼氫化鈉及氫氣(其係在例如鈀、鉑、鎳、釕、銠及其化合物,其尤其位於載體上或呈氧化物形式之觸媒存在下)。 Among the reducing agents which can be used to carry out the reductive amination reaction of the compound of the formula (VI) with the compound of the formula (VII), mention may be made of (not to be construed as limiting) sodium triacetoxyborohydride, sodium cyanoborohydride and hydrogen. (It is for example in the presence of palladium, platinum, nickel, rhodium, ruthenium and their compounds, especially in the presence of a catalyst or in the form of an oxide in the form of an oxide).
較佳地,用於進行式(VI)化合物與式(VII)化合物之還原胺化反應之還原劑係於碳上鈀存在下之氫氣。 Preferably, the reducing agent used to carry out the reductive amination reaction of the compound of formula (VI) with the compound of formula (VII) is hydrogen in the presence of palladium on carbon.
較佳於0.5至1.5 bar之氫氣壓力下進行式(VI)化合物與式(VII)化合物之還原胺化反應。 The reductive amination reaction of the compound of the formula (VI) with the compound of the formula (VII) is carried out preferably under a hydrogen pressure of from 0.5 to 1.5 bar.
在可用於進行式(VI)化合物與式(VII)化合物之還原胺化反應之溶劑中,可提及(不意味任何限制)四氫呋喃、二氯甲烷及1,2-二氯乙烷、乙酸酯、醇類(較佳係乙醇、甲醇或異丙醇)、甲苯及二甲苯。 Among the solvents which can be used to carry out the reductive amination reaction of the compound of the formula (VI) with the compound of the formula (VII), mention may be made of (not to be construed as limiting) tetrahydrofuran, dichloromethane and 1,2-dichloroethane, acetic acid. Esters, alcohols (preferably ethanol, methanol or isopropanol), toluene and xylene.
較佳地,用於進行式(VI)化合物與式(VII)化合物之還原胺化反應之溶劑包含乙醇及水之混合物。 Preferably, the solvent used to carry out the reductive amination reaction of the compound of formula (VI) with the compound of formula (VII) comprises a mixture of ethanol and water.
較佳於0℃至40℃之溫度下進行式(VI)化合物與式(VII)之化合物之還原胺化反應。 The reductive amination reaction of the compound of the formula (VI) with the compound of the formula (VII) is preferably carried out at a temperature of from 0 °C to 40 °C.
在可用於式(VIII)化合物與式(IX)化合物之反應的有機溶劑中,可提及(不意味任何限制)甲苯、二氯甲烷、2-甲基四氫呋喃、氯苯、1,2-二氯乙烷、氯仿及二噁烷。 Among the organic solvents which can be used in the reaction of the compound of the formula (VIII) with the compound of the formula (IX), mention may be made of (not to be construed as limiting) toluene, dichloromethane, 2-methyltetrahydrofuran, chlorobenzene, 1,2-di Ethyl chloride, chloroform and dioxane.
較佳地,式(VIII)化合物與式(IX)化合物之反應中所使用的有機溶劑係二氯甲烷。 Preferably, the organic solvent used in the reaction of the compound of the formula (VIII) with the compound of the formula (IX) is dichloromethane.
較佳於0℃至40℃之溫度下進行式(VIII)與式(IX)化合物之反應。 The reaction of the compound of the formula (VIII) with the compound of the formula (IX) is preferably carried out at a temperature of from 0 °C to 40 °C.
在可用於式(VIII)化合物與(IX)化合物之反應的鹼中,可提及(不意味任何限制)吡啶、DMAP及三級胺(例如三乙胺)、DIEA、N-甲基哌啶、DBU、DABCO、DBN及N-甲基嗎啉。 Among the bases which can be used in the reaction of the compound of the formula (VIII) with the compound of (IX), mention may be made of (not to be construed as limiting) pyridine, DMAP and tertiary amines (for example triethylamine), DIEA, N-methylpiperidine , DBU, DABCO, DBN and N-methylmorpholine.
較佳地,式(VIII)與式(IX)化合物之反應中所使用的鹼係三乙胺。 Preferably, the base is triethylamine used in the reaction of the compound of the formula (VIII) with the compound of the formula (IX).
在可用於進行式(X)化合物之環化作用以形成(V)化合物之酸中,可提及(不意味任何限制)濃硫酸、多磷酸、濃鹽酸水溶液、濃鹽酸之乙酸溶液、濃氫溴酸之乙酸溶液及甲磺酸。 Among the acids which can be used to carry out the cyclization of the compound of the formula (X) to form the compound (V), mention may be made of (not to be construed as limiting) concentrated sulfuric acid, polyphosphoric acid, concentrated aqueous hydrochloric acid, concentrated hydrochloric acid in acetic acid, concentrated hydrogen A solution of bromic acid in acetic acid and methanesulfonic acid.
較佳地,用於進行式(X)化合物之環化作用以形成式(V)化合物之酸係濃鹽酸之乙酸溶液。 Preferably, the cyclization of the compound of formula (X) is carried out to form an acetic acid solution of the acid-based concentrated hydrochloric acid of the compound of formula (V).
較佳於0℃至40℃之溫度下,在酸性介質中進行式(X)化合物之環化作用以形成式(V)化合物。 The cyclization of the compound of formula (X) is preferably carried out in an acidic medium at a temperature of from 0 ° C to 40 ° C to form a compound of formula (V).
式(VIII)及式(IX)化合物係新穎產物,其等可用作化學或醫藥工業(尤其係依伐布雷定、其與醫藥上可接受酸之加成鹽及其水合物之合成)中之合成中間物,且因此其等形成本發明之組成部分。 The compounds of formula (VIII) and formula (IX) are novel products which can be used in the chemical or pharmaceutical industry (especially in the synthesis of ivabradine, its addition salts with pharmaceutically acceptable acids and hydrates thereof) The intermediates are synthesized, and thus they form part of the invention.
DABCO:1,4-二氮雜雙環[2.2.2]辛烷 DABCO: 1,4-diazabicyclo[2.2.2]octane
DBN:1,5-二氮雜雙環[4.3.0]壬-5-烯 DBN: 1,5-diazabicyclo[4.3.0]non-5-ene
DBU:1,8-二氮雜雙環[5.4.0]十一-7-烯 DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DIEA:N,N-二異丙基乙胺 DIEA: N,N -diisopropylethylamine
DMAP:4-二甲基胺基吡啶 DMAP: 4-dimethylaminopyridine
IR:紅外 IR: infrared
以下實例說明本發明。 The following examples illustrate the invention.
使用具有Golden Gate ATR配件之Bruker Tensor 27紅外裝置記錄紅外光譜。將物質以純形式放置於平板上。 Infrared spectra were recorded using a Bruker Tensor 27 infrared device with a Golden Gate ATR accessory. The material is placed on the plate in pure form.
將5.3 g(25.5毫莫耳)1-[(7S)-3,4-二甲氧基雙環[4.2.0]辛-1,3,5-三烯-7-基]N-甲基-甲胺及6.8 g(25.5毫莫耳)2-(3-溴丙基)-1H-異吲哚-1,3(2H)-二酮溶解於23,mL丙酮中。將13 g(95毫莫耳,3.7當量)碳酸鉀添加至所得溶液中。隨後將該混合物回流加熱24小時。在恢復至室溫後,濾出該碳酸鉀且將濾液蒸發至乾。將殘留物溶於水中並使用二氯甲烷萃取。於MgSO4上乾燥有機相,過濾並蒸發至乾。獲得9.7 g淺黃色油狀預期產物。 5.3 g (25.5 mmol) of 1-[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]N-methyl- Methylamine and 6.8 g (25.5 mmol) of 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione were dissolved in 23 mL of acetone. 13 g (95 mmol, 3.7 equivalents) of potassium carbonate was added to the resulting solution. The mixture was then heated under reflux for 24 hours. After returning to room temperature, the potassium carbonate was filtered off and the filtrate was evaporated to dry. The residue was dissolved in water and extracted with dichloromethane. In the organic phase was dried over MgSO 4, filtered and evaporated to dryness. The expected product was obtained in 9.7 g of pale yellow oil.
產率=97% Yield = 97%
IR:v=2782、1770、1704、1206、836、718 cm-1。 IR: v = 2782, 1770, 1704, 1206, 836, 718 cm -1 .
將先前步驟之9.7 g(24.58毫莫耳)鄰苯二甲醯亞胺溶解於100 mL乙醇中。添加2.7 mL(36.87毫莫耳,1.5當量)水合肼,且回流加熱4小時。在恢復至室溫後,添加100 mL鹽酸水溶液(4 N);於溫下攪拌該混合物1小時並在玻璃料上過濾。然後蒸發濾液(移除乙醇)。隨後使用醚沖洗水相兩次並藉由添加冷卻狀態之濃氫氧化鈉溶液使其達到pH 9。 用二氯甲烷進行3次萃取,且隨後使用水沖洗合併的有機相,於MgSO4上乾燥,過濾並蒸發至乾。獲得4.9 g淺黃色油狀預期產物。 The previous step of 9.7 g (24.58 mmol) of phthalimide was dissolved in 100 mL of ethanol. 2.7 mL (36.87 mmol, 1.5 equivalents) of hydrazine hydrate was added and heated under reflux for 4 hours. After returning to room temperature, 100 mL of aqueous hydrochloric acid (4 N) was added; the mixture was stirred at room temperature for 1 hour and filtered on glass frit. The filtrate was then evaporated (ethanol removed). The aqueous phase was then rinsed twice with ether and brought to pH 9 by the addition of a concentrated sodium hydroxide solution in a cooled state. Extracted with methylene chloride for three times, rinsed with water and then the combined organic phases were dried on MgSO 4 to, filtered and evaporated to dryness. The desired product was obtained in 4.9 g of pale yellow oil.
產率=75% Yield = 75%
IR:v=3366、3302、1591 cm-1。 IR: v = 3366, 3302, 1591 cm -1 .
將1 g(3.7毫莫耳)N-{[(7S)-3,4-二甲氧基雙環[4.2.0]辛-1,3,5-三烯-7-基]甲基}-N-甲基丙烷-1,3-二胺溶解於20 mL乙醇中。先後添加520 mg(0.45 mL)乙二醛1,1-二甲基縮醛之60%水溶液及100 mg 10% Pd/C。於大氣壓及室溫下,使該反應混合物氫化12小時。濾出該觸媒並將濾液蒸發至乾。獲得1.2 g油狀預期產物。 1 g (3.7 mmol) of N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]oct-1,3,5-trien-7-yl]methyl}- N-methylpropane-1,3-diamine was dissolved in 20 mL of ethanol. 520 mg (0.45 mL) of a 60% aqueous solution of glyoxal 1,1-dimethylacetal and 100 mg of 10% Pd/C were added. The reaction mixture was hydrogenated at atmospheric pressure and room temperature for 12 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. 1.2 g of the expected product was obtained as an oil.
產率=90% Yield = 90%
IR:v=1207、1508、834 cm-1。 IR: v = 1207, 1508, 834 cm -1 .
製備含於80 mL CH2Cl2中之6.3 g(17.9毫莫耳)來自先前步驟之縮醛之溶液。將5 mL三乙胺(35.8毫莫耳,2當量)添加至所得溶液中,然後使其冷卻至0℃。隨後將含於40 mL二氯甲烷中之3.8 g(17.9毫莫耳)高藜蘆氯之溶液逐滴添加至其中。然後於室溫下進行3小時攪拌。用水稀釋該混合物並藉由二氯甲烷萃取。於MgSO4上乾燥該有機相,過濾並蒸發至乾。獲得10 g油且於500 g矽膠上使其純化(洗脫液=CH2Cl2/EtOH:90/10)。獲得8.5 g棕色油狀預期產物。 A solution of 6.3 g (17.9 mmol) of the acetal from the previous step contained in 80 mL of CH 2 Cl 2 was prepared. 5 mL of triethylamine (35.8 mmol, 2 equivalents) was added to the resulting solution, which was then cooled to 0 °C. A solution of 3.8 g (17.9 mmol) of high cucurbit chlorine contained in 40 mL of dichloromethane was then added dropwise thereto. It was then stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with dichloromethane. MgSO 4 in the organic phase was dried, filtered and evaporated to dryness. 10 g of oil was obtained and purified on 500 g of hydrazine (eluent = CH 2 Cl 2 /EtOH: 90/10). The desired product was obtained in 8.5 g of brown oil.
產率=90% Yield = 90%
IR:v=1627、1207、1124、1071、1049、1027 cm-1。 IR: v = 1627, 1207, 1124, 1071, 1049, 1027 cm -1 .
在室溫下,將1 g(1.9毫莫耳)來自先前步驟之縮醛添加至10 mL乙酸及10 mL濃鹽酸之混合物中。於25℃下攪拌1小時。藉由添加冰及氫氧化鈉水溶液(20%)使該溶液達到pH 9。然後藉由二氯甲烷萃取該混合物。用水沖洗該有機相,於MgSO4上乾燥,過濾並蒸發至乾。獲得1 g油且於40 g矽石上藉由急驟層析法(MerckTM管柱,洗脫液=CH2Cl2/EtOH:95/5)使其純化。獲得270 mg具有大於99%之光學純度之油狀預期產物。 1 g (1.9 mmol) of the acetal from the previous step was added to a mixture of 10 mL of acetic acid and 10 mL of concentrated hydrochloric acid at room temperature. Stir at 25 ° C for 1 hour. The solution was brought to pH 9 by the addition of ice and aqueous sodium hydroxide (20%). The mixture was then extracted by dichloromethane. The organic phase was washed with water, dried on MgSO 4, filtered and evaporated to dryness. To obtain 1 g of oil and 40 g on Silica by flash chromatography (Merck TM column, eluent = CH 2 Cl 2 / EtOH: 95/5) was purified. 270 mg of the oily expected product with an optical purity greater than 99% were obtained.
產率=31% Yield = 31%
IR:v=1656、836、760 cm-1。 IR: v = 1656, 836, 760 cm -1 .
自前述實例5之化合物開始,藉由再現專利說明書EP 0 534 859之實例1之步驟D獲得該標題化合物。 Starting from the compound of Example 5 above, the title compound was obtained by the step D of Example 1 of the patent specification EP 0 534 859.
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FR1100446A FR2971507B1 (en) | 2011-02-14 | 2011-02-14 | NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
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TW201307293A true TW201307293A (en) | 2013-02-16 |
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TW101104569A TWI430993B (en) | 2011-02-14 | 2012-02-13 | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
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EP (1) | EP2487158B1 (en) |
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KR (1) | KR101372389B1 (en) |
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NZ (1) | NZ598138A (en) |
PE (1) | PE20121741A1 (en) |
PL (1) | PL2487158T3 (en) |
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UA (1) | UA110326C2 (en) |
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CN102827019B (en) * | 2012-09-12 | 2014-12-10 | 江苏宇田生物医药科技有限公司 | One group of novel benzene cyclobutane compounds and application of novel benzene cyclobutane compounds in chemical synthesis |
CN103848789B (en) * | 2012-11-29 | 2016-05-18 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of Ivabradine |
CN104447553B (en) * | 2013-09-22 | 2017-02-01 | 广东众生药业股份有限公司 | Preparation method for ivabradine and intermediate thereof |
CN104829470B (en) * | 2015-04-20 | 2017-08-25 | 江苏宇田医药有限公司 | One is combined into the midbody compound of Ivabradine and its application |
KR200488336Y1 (en) | 2017-01-04 | 2019-01-15 | 한전케이피에스 주식회사 | Disassembly and assembly device for actuator coupling of low pressure turbine |
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US179316A (en) * | 1876-06-27 | Improvement in processes of preparing and producing colored photographs on glass | ||
FR2681862B1 (en) | 1991-09-27 | 1993-11-12 | Adir Cie | NOVELS (BENZOCYCLOALKYL) ALKYLAMINES, THEIR PREPARATION PROCESS, AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
FR2868777B1 (en) * | 2004-04-13 | 2006-05-26 | Servier Lab | NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
FR2868775B1 (en) * | 2004-04-13 | 2008-04-11 | Servier Lab | NOVEL PROCESS FOR THE SYNTHESIS OF 1,3,4,5-TETRAHYDRO-2H-3-BENZAZEPIN-2-ONE DERIVATIVES AND THE APPLICATION TO THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
EP2460797A3 (en) * | 2006-11-30 | 2012-12-05 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
ES2528026T3 (en) * | 2007-05-30 | 2015-02-03 | Ind-Swift Laboratories Limited | Salts of crystalline ivabridine oxalate and polymorphs thereof |
FR2933975B1 (en) * | 2008-07-17 | 2011-02-18 | Servier Lab | NOVEL PROCESS FOR THE PREPARATION OF FUNCTIONALIZED BENZOCYCLOBUTENES, AND APPLICATION TO THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
CN101723897B (en) * | 2008-10-31 | 2011-11-16 | 齐鲁制药有限公司 | Method for synthesizing Ivabradine |
ES2402765T3 (en) * | 2008-12-22 | 2013-05-08 | Krka, D.D., Novo Mesto | Ivabradine preparation procedure |
FR2940287B1 (en) * | 2008-12-24 | 2010-12-24 | Servier Lab | NEW PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
FR2941695B1 (en) * | 2009-02-04 | 2011-02-18 | Servier Lab | NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
FR2943668B1 (en) | 2009-03-31 | 2011-05-06 | Servier Lab | NEW PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
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